Intensive efforts to develop an efficient systemic vaccine to contain the HIV/AIDS epidemic have met with limited success. This lack of success combined with the fact that primary infection often occurs via mucosal surfaces, and that the mucosa contains large numbers of activated CD4+ T-cells has shifted attention to the role of the mucosal immune system in HIV transmission and AIDS pathogenesis. This shift has been accelerated by the observation that CD4+ T cells in the intestinal mucosa are the initial targets for SIV infection and destruction. Furthermore, preservation of mucosal CD4+ T cells in animals immunized intrarectally has been shown to be an important correlate of vaccine effectiveness. We predict that a mucosal AIDS vaccine that incorporates both T helper and CTL epitopes in conjunction with immuno-enhancing molecules designed to stimulate the immune response towards generating HIV/SIV specific CTL, will be highly efficient in controlling the virus infection in its primary reservoir, e.g. gut-associated lymphoid tissue (GALT) and may protect the host against subsequent challenge. We hypothesize that an efficient HIV/SIV vaccine should be directed primarily towards stimulating effector cells residing within GALT to protect the primary target tissues from infection and viral replication. To address this, we propose the following specific aims: 1) To test in vivo the efficiency of novel mucosal vaccination systems which comprise HIV-1 env/SIVgag specific synthetic-peptides or proteins, and LT(R192G) adjuvant incorporated into immuno-stimulating complexes (ISCOMs) in rhesus macaques subsequently challenged with simian-human immunodeficiency viruses (SHIVs). 2) To determine the potential correlate(s) of individual immune response components (T helper, CTL and humoral responses) with virus clearance, load, persistence of virus in tissues, and clinical signs associated with AIDS. To achieve this both vaccinated and control animals will be challenged with simian-human immunodeficiency viruses (SHIVs). Summary: By utilizing the nonhuman primate model of AIDS this proposed study will identify novel vaccine strategies that may induce effective mucosal and systemic immune responses, hence protecting from HIV/SIV infection and AIDS. Moreover, this proposed study might identify important correlates of protective immune responses that will be useful in designing effective therapeutic strategies.